2-Arachidonoyl glycerol (2-AG) is known to be one of the most important endocannabinoids, and is a lipid transmitter that serves as endogenous ligand for cannabinoid G-protein coupled receptors CB1 and CB2. (Long et al., Proc. Natl. Acad. Sci., 106:20270-20275 (2009)). 2-AG is primarily degraded by the enzyme monoacylglycerol lipase (MAGL). 2-AG and MAGL are components of the endogenous cannabinoid system, which regulates a diverse number of physiological processes including, but not limited to, pain, cognition, emotionality, neurogeneration, feeding and inflammation. (Di Marzo et al., Chem Biol, 14:741-756 (2007). It was further reported that endogenous cannabinoid system can play a role in regulating a variety of conditions that include, but are not limited to, inflammation, metabolic disorders (e.g., obesity-related conditions and wasting conditions such as cachexias and anorexia), disorders of the central nervous system (e.g., disorders associated with neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, movement disorders such as basal ganglia disorders, amylotrophic lateral sclerosis, Alzheimer's disease, epilepsy, mental disorders such as anxiety, depression, learning disorders and schizophrenia, sleep disorders such as insomnia, nausea and/or emesis, and drug addiction), cardiac disorders (e.g., hypertension, circulatory shock, myocardial reperfusion injury and atherosclerosis) and glaucoma (See, e.g., Pacher et al., Pharmacological Reviews, 58:389-462(2006); and Pillarisetti et al., Drug Discovery Today, 597:1-14(2009)). Thus, a need exists for an effective inhibitor for MAGL as a therapy for a wide variety of endogenous cannabinoid system related conditions or disorders.
It has been reported that MAGL is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth (Nomura et al., Cell, 140:49-61 (2010)). Overexpression of MAGL is found to increase the free fatty acid (FFA) levels and the aggressiveness of cancer cells—phenotypes that are reversed by an MAGL inhibitor. Id. Thus, a need also exists for an effective inhibitor for MAGL as a therapy for cancer.